Degradation of The Receptor for Advanced Glycation End Products (RAGE) - A Novel Mechanism in Lung Epithelial Cell Injury

晚期糖基化终末产物受体 (RAGE) 的降解——肺上皮细胞损伤的一种新机制

• 批准号: 9326410
• 负责人: John W Evankovich
• 金额: $ 6.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2019-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326410
• 关键词: Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Advanced Glycosylation End Products; Affect; Alpha Cell; Alveolar; Award; Biochemical; Biological; Biological Markers; Biology; Cell membrane; Cell physiology; Cells; Cellular biology; Characteristics; Charge; Clinical; Critical Care; DNA; Data; Degradation Pathway; Development; Diffuse; Doctor of Philosophy; Epithelial; Epithelial Cells; Epithelium; Extracellular Matrix; Functional disorder; Half-Life; Host Defense; Hour; Hypersensitivity; Hypoxemia; Inflammation; Inflammatory; Injury; Laboratories; Ligands; Lung; Lysine; Lysosomes; Mediating; Mediator of activation protein; Medicine; Membrane; Mentors; Modeling; Molecular; Molecular Profiling; National Research Service Awards; Natural Immunity; Pathologic; Pathway interactions; Pharmacology; Phenotype; Physicians; Physiology; Plasmids; Post-Translational Protein Processing; Process; Proteins; Recruitment Activity; Research Methodology; Research Personnel; Resistance; Respiratory Failure; Science; Scientist; Serine; Serum; Severities; Signal Transduction; Site; Small Interfering RNA; Study of serum; Survivors; Time; Training; Translational Research; Ubiquitin; Ubiquitination; Universities; Work; career; cell injury; insight; lung injury; member; mortality; novel; novel strategies; overexpression; pre-clinical; programs; protein degradation; receptor; response; skills; small molecule; translational scientist; ubiquitin-protein ligase

This application is for a Ruth L. Kirschstein National Research Service Award (NRSA) entitled “Degradation of The Receptor for Advanced Glycation End Products (RAGE) by FBXO10 – A Novel Mechanism in Lung Epithelial Cell Injury”. I am a physician in pulmonary and critical care medicine at the University of Pittsburgh. I am applying for this award to acquire advanced training in molecular physiology and cell biology, as well as new training in translational research methods and regulatory science, to develop my career as a physician scientist focused on the study of Acute Lung Injury. The main objective of my proposal is to determine how a novel RAGE degradation pathway in lung epithelial cells modulates severe lung injury. RAGE is a cell membrane receptor enriched in lung epithelia, and contributes to epithelial cell injury by weakening attachment to the extracellular matrix (ECM) and amplifying inflammatory signals in response to circulating ligands encountered in excessive inflammatory conditions such as Acute Respiratory Distress Syndrome (ARDS). Our preliminary data indicate that RAGE is degraded in lung epithelial cells in a mechanism dependent on the post-translational modification of ubiquitination. Furthermore, we have preliminarily identified a novel ubiquitin-transferring subunit termed FBXO10 responsible for targeting RAGE for degradation, and also show that RAGE is degraded in response to a ligand elevated in ARDS, CpG DNA. The aims of this study are: 1.) To determine if RAGE is ubiquitinated and degraded in lung epithelial cells by the E3-Ligase subunit FBXO10, and 2.) To determine the mechanism and biologic effect of RAGE degradation in pulmonary epithelial cells. These studies will provide insight into a novel pathologic model whereby RAGE degradation, regulated by FBXO10 mediated protein ubiquitination, controls epithelial cell detachment and excessive inflammation. FBXO10 mediated ubiquitination and degradation of RAGE may contribute to the histopathologic phenotype of “diffuse alveolar damage” characteristic of ARDS by promoting epithelial cell detachment from the ECM. Thus, modulating RAGE degradation may be a novel strategy to render epithelial cells more resistant to injury and contribute to an unmet need in novel ARDS therapies. This project will provide me advanced skills in molecular physiology and cell biology, and I will be trained in translational research methodologies and regulatory science to strengthen my development into an independent investigator. My work will be completed within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, which is dedicated to the development of physician scientists. I have committed mentoring from our Division Chief Dr. Rama Mallampalli as well as a PhD cosponsor in Dr. Bill Chen. Additionally, my mentoring committee includes Dr. Janet Lee, MD – an expert in innate immunity and host defense, and Dr. Bryan McVerry – a translational scientist and member of the Acute Lung Injury Center of Excellence in charge of the clinical ALI program.

这份申请是露丝·L Kirschstein国家研究服务奖（NRSA），题为“ FBXO 10介导的晚期糖基化终末产物受体--肺内的一种新机制 上皮细胞损伤”。我是芝加哥大学的一名肺病和重症监护医学医生， 匹兹堡我申请这个奖项是为了获得分子生理学和细胞生物学方面的高级培训， 以及转化研究方法和监管科学的新培训，以发展我的职业生涯， 医生科学家专注于急性肺损伤的研究。我的建议的主要目的是 确定肺上皮细胞中的一种新的β-内酰胺降解途径如何调节严重的肺 损伤E2是一种在肺上皮细胞中富集的细胞膜受体，并通过以下途径促进上皮细胞损伤： 减弱与细胞外基质（ECM）的附着并响应于炎症信号放大， 在过度炎症性疾病如急性呼吸窘迫中遇到的循环配体 综合征（ARDS）。我们的初步数据表明，在肺上皮细胞中， 泛素化的翻译后修饰机制。此外，我们还 初步鉴定了一个新的泛素转移亚基FBXO 10，负责靶向 这些结果表明，在ARDS中，CpG DNA的降解是响应于配体CpG DNA的升高而降解的。的 本研究的目的是：（1）。为了确定在肺上皮细胞中， E3-连接酶亚基FBXO 10和2.）目的：探讨玉米秸秆降解的机理和生物学效应， 肺上皮细胞这些研究将提供一种新的病理模型， 由FBXO 10介导的蛋白泛素化调节的降解控制上皮细胞脱离， 过度炎症。FBXO 10介导的泛素化和降解的β-淀粉样蛋白可能有助于 急性呼吸窘迫综合征弥漫性肺泡损害组织病理学表型 与ECM分离。因此，调节β-淀粉样蛋白降解可能是一种新的策略， 细胞对损伤更有抵抗力，并有助于新的ARDS治疗中未满足的需求。该项目将 提供我先进的技能，在分子生理学和细胞生物学，我将接受培训，翻译 研究方法和监管科学，以加强我的发展成为一个独立的 调查员我的工作将在肺、过敏和重症监护医学部完成， 匹兹堡大学致力于培养医学科学家。我犯了 我们的部门主管拉马Mallampalli博士以及比尔博士的博士共同赞助人的指导 尘此外，我的指导委员会还包括医学博士珍妮特·李（Janet Lee）--先天免疫专家， 主持人辩护，和布莱恩·麦克维里博士-一个翻译科学家和急性肺损伤中心的成员， 卓越负责临床ALI项目。